The present invention relates to medical devices used to electrically stimulate the digestive system, and more specifically to devices employed to electrically stimulate portions of the digestive system and/or the vagus nerve to increase the acidity of gastric acid secretions and/or increase the amount of gastric acid secretions produced by the stomach.
The medical device industry produces a wide variety of electronic and mechanical devices for treating patient medical conditions. Depending upon a patient's medical condition, medical devices may be surgically implanted or connected externally to the patient. Physicians use medical devices alone or in combination with drug therapies and surgery to treat patient medical conditions. For some medical conditions, medical devices provide the best, and sometimes the only, therapy to treat a medical condition and restore an individual to a more healthful condition and a fuller life. One type of medical device applied to treat conditions receptive to neurological therapy is an implantable neurostimulator (hereafter “INS”). An INS applies an electrical signal to the nervous system to create a response such as reducing patient pain or influencing a body organ, and may also be employed to apply an electrical signal to the enteric nervous system.
The digestive system is composed of the digestive tract, accessory organs and the enteric nervous system, and functions to prepare food for absorption and use by the body. The enteric nervous system is the digestive system's nervous system, and it functions to both receive and transmit information. This system receives neurological information from the digestive system through afferent nerves, and issues instructions through efferent nerves. Gastric myoelectrical activity is described by Kenneth Koch et al. in Electrogastrography, “An Illustrated Guide To Gastrointestinal Motility,” 2nd Ed., pp. 290-307 (1993). The vagus nerve contains both afferent and efferent nerves and provides nervous system connectivity between digestive system organs, including between the stomach and brain. The gastric frequency of a patient is generally about 3.0 cycles per minute. The enteric nervous system is believed to exert some control over gastric acid secretion functions.
Hypochlorhydria is the underproduction of hydrochloric acid (HCl) by the stomach. HCl acid is responsible for two important functions: (1) breaking down complex proteins directly, and (2) working as an activator for the enzyme pepsin, which further breaks down protein. Due to similarities between the symptoms of gastric hyperchlorhydria and hypochlorhydria, patients with underlying hypochlorhydria often receive inappropriate therapy for hyperchlorhydria. Morihara, et al., suggest that 40% of the population over the age of 50 is hypochlorhydric. In these patients, drugs and dosage forms which require an acidic environment for dissolution or release may be poorly assimilated (Russell, et al). Typical therapies for hypochlorhydria includes supplemental HCl ingestion (Betaine HCl). Compliance and correct dosing—especially in elderly patients—may be difficult.
Green and Graham report that hypochlorhydria is often concomitant with a number of other gastrointestinal disorders. There is a close association between gastritis, gastric carcinoma, Heliobacter pylori infection and hypochlorhydria in the elderly.
Grundy and Scratcherd achieved maximal secretion at 10 Hz using 500 microsecond “supramaximal” stimulation. They noted that this effect disappeared as stimulation frequencies were increased beyond 30 impulses/second. Tashima, et. al increased gastric acid output from 2.3+/−0.4 micro-equivalents/5 minutes to 8.8+/−1.4 micro-equivalents/5 minutes in male Sprague-Dawley rats when stimulating the peripheral end of the left vagus nerve with square-wave pulses (PW=2 ms, f=3 Hz, amplitude=0.5 mA). While many journal articles use low-rate vagal stimulation to increase acid output, the primary intent is often to test another physiologic process (i.e. the effects of low-rate vagal stimulation in a diabetic rats, or the effects of a novel anti-secretory agent when low-rate stimulation is used as the secretagogue).
The gastro-intestinal tract has an extensive nervous system of its own called the enteric nervous system. There are two main plexuses in the enteric system:                (1) An outer plexus—called the myenteric plexus—that lies between the longitudinal and circular muscle layers, and;        (2) An inner plexus—called the submucosal plexus—that lies in the submucosa.        
The myenteric plexus primarily controls the gastrointestinal movements, and the submucosal plexus mainly controls gastrointestinal secretion and local blood flow. The sympathetic and parasympathetic fibers connect with both the plexuses, and can further activate or inhibit gastrointestinal function (see FIG. 5a).
More than a dozen neurotransmitters have been identified in the gastro-intestinal tract. Acetylcholine (a parasympathetic neurotransmitter) typically excites gastrointestinal activity and norepinephrine (a sympathetic neurotransmitter) typically inhibits gastrointestinal activity.
The cranial parasympathetic fibers extensively innervate the stomach, and are transmitted almost entirely in the vagus nerves that run proximal to the esophagus. The sympathetic fibers to the gastro-intestinal tract originate in the spinal cord between segments T-5 and L-2. Stimulation of these fibers result in an inhibitory effect by norepinephrine which can block movement of food through the gastro-intestinal tract.
Many afferent sensory nerve fibers arise in the gut. These nerves can be stimulated by (1) irritation of the gut mucosa, (2) excessive distention of the gut, or (3) presence of specific chemical substances in the gut. Almost 80% of nerve fibers in the vagus bundle are afferent rather than efferent. These fibers transmit afferent signals into the medulla, which in turn initiates many reflex signals that control gastro-intestinal functions. As such, stimulation of the vagus nerve may directly affect the gastro-intestinal tract through efferent nerve capture or through a more circuitous route involving the medulla.
As shown in FIG. 5b, the wall of the stomach is lined with billions of single-cell mucous glands. These cells extrude mucous directly onto the epithelial surface to act as a lubricant and prevent auto-digestion. There are also two types of tubular glands that exist, the oxyntic glands and the pyloric glands. The oxyntic glands secrete hydrochloric acid (HCl) and the pyloric glands secrete the hormone gastrin. The oxyntic glands are located on the inside surfaces of the body and fundus of the stomach, and the pyloric glands are located in the antral portion of the stomach. Gastrin and histamine are potent stimulants for acid release by the parietal cells in the oxyntic glands; the parietal cells secrete a highly acidic solution that contains about 160 millimoles of HCl per liter. A synthetic form of gastrin known as pentagastrin is composed of the terminal four amino acids of natural gastrin plus the amino acid alanine. It has all the same physiological properties as natural gastrin.
It has been shown that relatively slow stimulation of the vagi (4-8 Hz) induces maximal acid secretion in cats (Sjodin, 1975). Pharmaceutical companies frequently use this model to test acid-suppressing drugs. Grundy and Scratcherd, however, found that higher rate electrical stimulation (120 Hz) of the vagus nerve significantly reduced acid production versus basal output in ferrets. In their experiment, they performed a bilateral vagotomy in the neck and stimulated the thoracic vagi via a left thoracotomy. The stimulation regime they applied was “physiologic” (a taped replica of natural vagal activity), “burst” (60 or 120 Hz, 500 microsecond pulse width), or “continuous” (6 Hz). Their data showed that continuous low-rate stimulation increased acid output relative to the “taped” physiologic stimulation, while burst stimulation significantly decreased acid output.
Some prior art publications relating to the present invention are as follows:    Kenneth Koch et al., “An Illustrated Guide To Gastrointestinal Motility,” Electrogastrography, 2nd Ed., pp. 290-307 (1993).    Kenneth Koch et al., “Functional Disorders of the Stomach,” Seminars in Gastrointestinal Disease, Vol. 7, No. 4, 185-195 (October 1996).    Kenneth Koch, “Gastroparesis: Diagnosis and Management,” Practical Gastroenterology (November 1997).    Babajide Familoni et al., “Efficacy of Electrical Stimulation at Frequencies Higher than Basal Rate in Mayine Stomach,” Digestive Diseases and Sciences, Vol. 42, No. 5 (May 1997).    Babajide O. Familoni, “Electrical Stimulation at a Frequency Higher than Basal Rate in Human Stomach,” Digestive Diseases and Sciences, Vol. 42, No. 5 (May 1997).    Grundy, D. and Scratcherd, T., “Effects of stimulation of the vagus nerve in bursts on gastric acid secretion and motility in the anaesthetized ferret,” J. Physiol., 333: 451-461, 1982.    Sasaki, N., et al., “Selective action of a CCK-B/gastrin receptor antagonist, S-0509, on pentagastrin-, peptone meal- and beer-stimulated gastric acid secretion in dogs,” Aliment. Pharmacol. Ther., 14: 479-488, 2000.    Sjodin, L., “Gastric acid responses to graded vagal stimulation in the anaesthetized cat,” Digestion, 12(1): 17-24, 1975.    Physician's Manual, NeuroCyberonics Prosthesis, Bipolar Lead, Model 300, September, 2001.    U.S. Pat. No. 5,188,104 to Wernicke et al. for “Treatment of Eating Disorders by Nerve Stimulation.”    U.S. Pat. No. 5,231,988 to Wernicke et al. for “Treatment of Endocrine Disorders by Nerve Stimulation.”    U.S. Pat. No. 5,263,480 to Wernicke et al. for “Treatment of Eating Disorders by Nerve Stimulation.”    U.S. Pat. No. 5,292,344 to Douglas for “Percutaneously placed electrical gastrointestinal pacemaker INSy system, sensing system, and pH monitoring system, with optional delivery port.”    U.S. Pat. No. 5,423,872 to Cigaina for “Process and Device for Treating Obesity and Syndrome Motor Disorders of the Stomach of a Patient.”    U.S. Pat. No. 5,540,730 to Terry for “Treatment of motility disorders by nerve stimulation.”    U.S. Pat. No. 5,690,691 to Chen for “Gastro-intestinal pacemaker having phased multi-point stimulation.”    U.S. Pat. No. 5,716,385 to Mittal for “Crural diaphragm pacemaker and method for treating esophageal reflux disease.”    U.S. Pat. No. 5,836,994 to Bourgeois for “Method and apparatus for electrical stimulation of the gastrointestinal tract.”    U.S. Pat. No. 5,925,070 to King et al. for “Techniques for adjusting the locus of excitation of electrically excitable tissue.”    U.S. Pat. No. 5,941,906 to Barreras et al. for “Implantable, modular tissue INS.”    U.S. Pat. No. 6,083,249 to Familoni for “Apparatus for sensing and stimulating gastrointestinal tract on-demand”    U.S. Pat. No. 6,097,984 to Douglas for “System and method of stimulation for treating gastro-esophageal reflux disease.”    U.S. Pat. No. 6,238,423 to Bardy for “Apparatus and method for treating chronic constipation.”    U.S. Pat. No. 6,381,496 to Meadows et al. for “Parameter context switching for an implanted device.”    U.S. Pat. No. 6,393,325 to Mann et al. for “Directional programming for implantable electrode arrays.”    U.S. Pat. No. 6,449,511 to Mintchev for “Gastrointestinal electrical INS having a variable electrical stimulus.”    U.S. Pat. No. 6,453,199 to Kobosev for “Electrical Gastro-Intestinal Tract INS.”    U.S. Pat. No. 6,516,227 to Meadows et al. for “Rechargeable spinal cord INS system.”    U.S. Patent Application Publication No. 2002 165589 for “Gastric Treatment and Diagnosis Device and Method.”    U.S. Patent Application Publication No. 2003 014086 for “Method and Apparatus for Electrical Stimulation of the Lower Esophageal Sphincter.”    U.S. Patent Application Publication No. 2002 116030 for “Electrical stimulation of the Sympathetic Nerve Chain.”    U.S. Patent Application Publication No. 2002 193842 for “Heartburn and Reflux Disease Treatment Apparatus.”    U.S. Patent Application Publication No. 2002 103424 for “Implantable Medical Device Affixed Internally within the Gastrointestinal Tract.”    U.S. Patent Application Publication No. 2002 198470 for “Capsule and Method for Treating or Diagnosing the Intestinal Tract.”    PCT Patent Application WO 0089655 for “Sub-Mucosal Gastric Implant Device and Method.”    PCT Patent Application WO 0176690 for “Gastrointestinal Electrical Stimulation.”    PCT Patent Application WO 02087657 for “Gastric Device and Suction Assisted Method for Implanting a Device on a Stomach Wall.”    PCT Patent Application WO 0238217 for “Implantable Neuromuscular INS for Gastrointestinal Disorders.”
All patents and technical papers listed hereinabove are hereby incorporated by reference herein, each in its respective entirety. As those of ordinary skill in the art will appreciate readily upon reading the Summary of the Invention, Detailed Description of the Preferred Embodiments and Claims set forth below, at least some of the devices and methods disclosed in the patents and publications listed hereinabove may be modified advantageously in accordance with the teachings of the present invention. The foregoing and other objects, features and advantages, which will now become more readily apparent by referring to the following specification, drawings and claims, are provided by the various embodiments of the present invention.